CFTR-Based Gene Therapy for Cystic Fibrosis Yields Promising Results in Clinical Trial

A study recently published in the journal The Lancet Respiratory Medicine revealed encouraging results of a phase 2b clinical trial assessing the safety and efficacy of a non-viral gene therapy based on a gene defective in cystic fibrosis (CF) patients. The study is entitled “Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial” and was performed by a team led by researchers at the Imperial College London, the University of Edinburgh, the University of Oxford, the Royal Hospital for Sick Children and the Western General Hospital in the United Kingdom.

CF is a rare, life-threatening genetic disease in which a defective gene called cystic fibrosis transmembrane conductance regulatory (CFTR) induces a salt imbalance, causing the body to form unusually thick, sticky mucus that can obstruct the airways and promote dangerous lung infections resulting in serious respiratory and also gastrointestinal manifestations. The majority of the CF patients die due to respiratory failure. It is estimated that almost 75,000 individuals worldwide suffer from CF, including 30,000 individuals in the United States and 10,000 in the United Kingdom.

Since the CFTR gene was discovered and cloned, gene therapy to introduce a normal copy of the gene has been a possibility for CF treatment. In the study, researchers conducted a randomized, double-blind, placebo-controlled, phase 2b trial (NCT01621867) to assess the clinical efficacy of a non-viral CFTR gene-liposome complex (pGM169/GL67A) as a delivery system for a functional CFTR gene in the airways of patients with CF.

In total, 136 CF patients aged 12 or older from two medical centers (London and Edinburgh) were given monthly doses of either the CFTR gene therapy (5 mL of nebulized pGM169/GL67A) or a placebo for a period of one year (June 2012 to June 2013). Researchers found a modest but significant clinical benefit in patients receiving the pGM169/GL67A in comparison to the placebo group one year after treatment. CF patients under gene therapy had a stable lung function while CF patients in the placebo group experienced deterioration. No significant adverse events related to the treatment were reported.

“Patients who received the gene therapy showed a significant, if modest, benefit in tests of lung function compared with the placebo group; there were no safety concerns. Whilst the effect was inconsistent, with some patients responding better than others, the results are encouraging, laying the groundwork for further trials which we hope could improve the effect,” said the study’s co-lead author Dr. Eric Alton in a news release.

The research team showed for the first time that a non-viral gene therapy based on the replacement of the defective CFTR gene in the lungs of CF patients can have a beneficial effect on disease progression, halting lung function decline. The team suggests that further research is, however, required to improve the therapy’s effectiveness.

“We are looking to undertake follow-up studies assessing higher, more frequent doses as well as combinations with other treatments,” said Dr. Alton. “Publication of this trial is a landmark for CF patients and we are particularly grateful to the many patients across the UK who gave their time and effort to participate and make this collaborative venture a success.”

“Cystic Fibrosis can have a devastating effect on patients and families and this is an excellent development for people living with the condition. The government is absolutely committed to supporting new medical treatments and invests £1bn a year in health research. It is vital we are at the forefront of turning scientific discoveries into tangible benefits and affordable treatments for NHS [National Health Service] patients,” said the British Minister for Life Sciences George Freeman.

“We are committed to improving and transforming the lives of people with cystic fibrosis, and the results of this pioneering clinical trial are a promising development. Further clinical research is now needed before we can say that it is a viable clinical therapy but it is encouraging that a proof of concept has been established,” concluded the Chief Executive of the Cystic Fibrosis Trust Ed Owen. “This is an extraordinary time for therapeutic development in cystic fibrosis and the need is urgent to stop so many young lives being cut short because of this cruel condition. We will therefore continue to invest in innovative genetic research and to work with academic and industry partners to develop advancements which will make further progress towards our goal of a life unlimited by cystic fibrosis.”